tbuckley/cabot-search huggingface dataset:
Abstract 6505: ColoScape test: a molecular assay to detect early-stage colorectal cancer in plasma cell-free DNA
Authors: Hiromi Tanaka, Shuo Shen, Mauro Scimia, Larry Pastor, Jonathan Li, Andrew Y. Fu, Daniel Kim, Rui Ni, Aiguo Zhang, Michael Y. Sha
Journal: Cancer Research (2023)

Abstract Colorectal cancer (CRC) is the second most common cause of cancer deaths when men and women are combined in the U.S. Early detection in the precancerous stage is key to reducing the CRC morbidity and mortality rates. Thus, there is a critical need for a cost-effective, time-efficient, and convenient clinical tool for early CRC detection. We have developed a multiplex qPCR assay (ColoScapeTM) to detect CRC-associated genetic and epigenetic changes from liquid biopsy samples (i.e., cell-free DNA) using our proprietary QClamp® XNA technology. The QClamp® XNA technology is very unique and enables the ColoScapeTM assay to selectively amplify the mutant and methylated DNA target sequences by using a synthetic DNA analog XNA (Xenonucleic Acid). This study demonstrates the analytical performance for detecting low-abundant mutated and methylated gene copies, as well as assess the clinical performance using plasma cell-free DNA samples from patients with CRC or advanced adenomas (≥1 cm) and from individuals with normal colonoscopies. The ColoscapeTM test is currently designed to detect mutations in 8 genes with 61 mutations and 7 methylated markers. The test consists of two parts: (i) the detection of mutations in 8 genes (APC, KRAS, BRAF, TP53, CTNNB1, NRAS, SMAD4, and PIK3CA) and (ii) the detection of 7 methylation targeted genes. For the assay analytical performance, the ColoScapeTM test shows that XNA effectively suppressed the wild-type background amplifications and led to amplify mutation and methylation target sequences dominantly, providing a high level of analytical sensitivity and specificity. The ColoScapeTM test is highly reproducible with intra- and inter-assay coefficient of variation of &amp;lt;10% and the cross-reactivity within the assay was limited and negligible. The results for the assay analytical sensitivity indicated that each target could be detected between 0.1% and 0.5% variant allele frequency in 10 ng cfDNA. The preliminary assay clinical specificity and sensitivity were 100% (95% CI: 91.3-100%) and 86% (95% CI: 66-95%) respectively for CRC and 91% specificity (95% CI: 75%-98%) and 60% sensitivity (95% CI: 17%-93%) for advanced adenomas. In summary, the ColoScape test utilizing the XNA-based technology provides high sensitivity and high specificity to CRC and advanced adenomas with a great potential to be used as an early screening test. Citation Format: Hiromi Tanaka, Shuo Shen, Mauro Scimia, Larry Pastor, Jonathan Li, Andrew Y. Fu, Daniel Kim, Rui Ni, Aiguo Zhang, Michael Y. Sha. ColoScape test: a molecular assay to detect early-stage colorectal cancer in plasma cell-free DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6505.
Abstract 621: Aging dampens lymphoma-provoked phenotypic and epigenomic changes to the adaptive immune system
Authors: Rebecca S. Hesterberg, Chia-Ho Cheng, Jiqiang Yao, Xiaofei Song, Xiaoqing Yu, John L. Cleveland
Journal: Cancer Research (2023)

Abstract Lymphoma is a disease that principally afflicts older individuals and also impairs the immune system, yet how aging and cancer interact to affect the immune system remains poorly understood. This is particularly the case for malignancies that arise within hematopoietic tissues that closely interact with immune cells. We hypothesized that lymphoma-provoked changes to the adaptive immune system would differ based on age. To explore how the immune system is altered by both B-cell lymphoma and the aging process, we transplanted Eμ-Myc lymphoma B-cells into mice aged 6-12 weeks or 20-24 months. Interestingly, as marked by reduced splenomegaly and lymphoma cell numbers, tumor burden was significantly reduced in aged hosts, suggesting lymphoma cells grow more slowly in the aged tissue microenvironment. Further, while lymphoma progression provoked losses in total numbers of normal T-cells, NK-cells, and B-cells in young individuals, aged lymphocytes were surprisingly resistant to lymphoma. Similarly, profound phenotypic changes in T-cell subpopulations that are provoked by Eμ-Myc lymphoma in young individuals, such as increases in expression of CD44, CD69, PD-1, Foxp3, and Tox, were not manifest in lymphoma-bearing aged mice. In addition, immature NK cell population dynamics were altered by lymphomas differently among aged mice when compared to young mice. Finally, analyses of the chromatin state of enriched CD4+ T cells from young and aged mice by ATAC-seq revealed that the aging process provoked marked alterations in the epigenome, and that lymphoma only provoked significant changes to the epigenome among young CD4+ T cells. We conclude that aging-driven epigenetic alterations manifest in the adaptive immune system renders these cells surprisingly resilient to lymphoma-mediated immune suppression. Citation Format: Rebecca S. Hesterberg, Chia-Ho Cheng, Jiqiang Yao, Xiaofei Song, Xiaoqing Yu, John L. Cleveland. Aging dampens lymphoma-provoked phenotypic and epigenomic changes to the adaptive immune system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 621.
Abstract 1298: Single cell analysis of breast cancer progression and metastasis to lymph nodes reveals cancer cell plasticity and MHC class II-mediated immune regulation
Authors: Pin-Ji Lei, Ethel Pereira, Patrik Andersson, Zohreh Amoozgar, Jan Willem Van Wijnbergen, Meghan J. O'Melia, Hengbo Zhou, Sampurna Chatterjee, William Wee Ho, Jessica M. Posada, Ashwin Srinivasan Kumar, Satoru Morita, Charlie Chuang, Ilgin Ergin, Dennis Jones, Peigen Huang, Semir Beyaz, Timothy P. Padera
Journal: Cancer Research (2023)

Abstract Tumor-draining lymph nodes are critical sites for generating tumor antigen-specific T cells and are associated with durable immune responses. However, lymph nodes are often the first site of metastasis and lymph node metastases portend worse outcomes. Through cross species single cell gene expression analysis of breast cancer progression and metastasis to lymph nodes, we uncovered features that define the heterogeneity, plasticity, and immune evasion of cancer cells. Notably, a subpopulation of metastatic cancer cells in the lymph node were marked by high levels of MHC class II (MHC-II) gene expression both in mice and humans. Mechanistically, the IFN-γ and JAK/STAT signaling pathways mediate MHC-II expression in cancer cells. Ablation of IFNGR1/2 or CIITA, the transactivator of MHC-II, in cancer cells prevented tumor progression. Interestingly, MHC-II+ cancer cells lacked co-stimulatory molecule expression, engendered the expansion of regulatory T cells and blunted CD4+ effector T cells in the tumor draining lymph nodes and favor tumor progression. Overall, our data suggests that cancer cell plasticity during breast cancer progression and metastasis to lymph nodes endows metastatic cells with the ability to avoid immune surveillance. These data provide the basis for new opportunities to therapeutically stimulate anti-cancer immune responses against local and systemic metastases. Citation Format: Pin-Ji Lei, Ethel Pereira, Patrik Andersson, Zohreh Amoozgar, Jan Willem Van Wijnbergen, Meghan J. O'Melia, Hengbo Zhou, Sampurna Chatterjee, William Wee Ho, Jessica M. Posada, Ashwin Srinivasan Kumar, Satoru Morita, Charlie Chuang, Ilgin Ergin, Dennis Jones, Peigen Huang, Semir Beyaz, Timothy P. Padera. Single cell analysis of breast cancer progression and metastasis to lymph nodes reveals cancer cell plasticity and MHC class II-mediated immune regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1298.
Abstract 2717: A potent and highly tumor-selective KRAS inactivator for tumor targeting
Authors: Shihui Liu, Zehua Zuo, Jie Liu
Journal: Cancer Research (2023)

Abstract Cancer driver mutations in the RAS-RAF-MEK-ERK pathway occur in 46% of all human cancers. This has inspired the successful development of many small molecule inhibitors of BRAF and MEK. However, development of RAS small molecule inhibitors has not been successful in large part due to the lack of a sufficiently large and deep hydrophobic pocket in RAS proteins to allow for small molecule binding. Notably, in this regard, many bacterial pathogens have evolved potent protein toxins to disrupt the RAS-RAF-MEK-ERK pathway. Fortunately, these naturally designed potent toxins, such as anthrax toxin, Fortunately, these potent, naturally designed toxins, such as anthrax toxin and DUF5, can be structurally modified to achieve high tumor specificity. DUF5 (amino acids Glu3581-Gln4089) is a toxin effector domain of MARTX (a multifunctional-autoprocessing repeats-in-toxin) from Vibrio vulnificus. DUF5 was recently identified to be a specific and potent endopeptidase that cleaves and inactivates RAS. To address the above critical unmet medical needs, in this work, we have generated an anthrax toxin/DUF5-based, highly tumor-selective RAS inactivator and evaluated its anti-tumor activity in a variety of tumor models. This tumor-selective RAS inactivator can specifically bind to the major anthrax toxin receptor CMG2 on tumor cells and tumor stromal cells, and strictly relies on the simultaneous presence of two distinct tumor-associated proteases, MMPs and urokinase, to gain entry into tumor cells and tumor stromal cells to proteolytically inactivate RAS signaling, achieving potent selective targeting. Our data show that our tumor-selective RAS inactivator displays potent cytotoxicity to cancer cells whose survival depends on oncogenic RAS signaling. Our engineered toxin displayed potent in vivo antitumor activity to a range of tumors with oncogenic RAS mutations in syngeneic and human xenograft mouse tumor models. Therefore, we have developed a tumor-selective, safe, and highly potent RAS inactivator that has high potential for targeting tumors with oncogenic RAS mutations. Citation Format: Shihui Liu, Zehua Zuo, Jie Liu. A potent and highly tumor-selective KRAS inactivator for tumor targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2717.
Abstract 2241: Transcriptomic analysis of tetraspanins in colorectal cancer
Authors: Thanawat Suwatthanarak, Pariyada Tanjak, Amphun Chaiboonchoe, Onchira Acharayothin, Kullanist Thanormjit, Tharathorn Suwatthanarak, Watsaphon Tangkullayanone, Manop Pithukpakorn, Vitoon Chinswangwatanakul
Journal: Cancer Research (2023)

Abstract Introduction: Transmembrane proteins and their overexpression have been highly involved in malignancies. In particular, Tetraspanins (TSPANs)—a family of four-span transmembrane proteins—have been proposed as “master organizers” of multi-molecular membrane complexes by associating with specific partners and thus contributed to the progression of many cancer types. To date, transcriptomic analysis of all human TSPANs in colorectal cancer (CRC) has remained unclear. Here, we focused on utilizing next-generation RNA sequencing (RNA-Seq) to explore the expression level of TSPANs in primary tumor tissues of CRC, which is a complex disease and the second cause of cancer mortality worldwide. Experimental Procedures: Resected primary tumor tissues of CRC were collected from 100 patients along with the written informed consents. Later, total RNA was extracted from all frozen patient tissues. RNA-Seq of those RNA samples was next done before the transcriptomic analysis of TSPANs in CRC was performed. Immunofluorescence (IF) and Immunohistochemistry (IHC) stains were also employed to confirm the target protein expression in formalin-fixed paraffin-embedded tissue (FFPE) slides from CRC patients. Results: As a result of transcriptomic analysis of TSPANs in CRC tissues, among 33 human TSPANs, the high expression levels (transcript per million above the average of all TSPANs) of TSPAN1, TSPAN8, TSPAN24, TSPAN29 and TSPAN30 were observed in the patient-derived CRC tissues. Notably, the expression level of TSPAN8 was comparable with that of EPCAM, which is a well-known tumor marker. Moreover, the high expression of TSPAN8 protein could be clearly observed in both IF and IHC-stained FFPE slides from CRC patients. Our result highlights the possible relevance of these overexpressed TSPANs in CRC development. Conclusions: This study is the first RNA-Seq-based transcriptomic analysis of all human TSPANs in CRC. Our finding suggests the significant overexpression of particular TSPANs, especially TSPAN8, in CRC. Further analyses will be beneficial for translational research in CRC. The overexpression of TSPANs may suggest a framework to further explore diagnostic, prognostic, and predictive surface biomarkers, therapeutic targets, and other applications for CRC. Citation Format: Thanawat Suwatthanarak, Pariyada Tanjak, Amphun Chaiboonchoe, Onchira Acharayothin, Kullanist Thanormjit, Tharathorn Suwatthanarak, Watsaphon Tangkullayanone, Manop Pithukpakorn, Vitoon Chinswangwatanakul. Transcriptomic analysis of tetraspanins in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2241.
Abstract 4696: Characterizing CD39 and CD73 cell subtypes in the tumor microenvironment using MultiOmyx
Authors: Courtney Todorov, Kevin Gallagher, Juliana Wortman, Harry Nunns, Erinn Parnell, Eric Leones, Elaine Yeung, Blair Russell, Flora Sahafi, Qingyan Au
Journal: Cancer Research (2023)

Abstract CD39 and CD73 are membrane bound enzymes that function together to convert extracellular adenosine 5’-triphospate (ATP)/adenosine diphosphate (ADP) into adenosine. CD39 first catalyzes ATP/ADP into adenosine monophosphate (AMP), which is then converted by CD73 into adenosine. Accumulation of extracellular adenosine creates an immunosuppressive tumor environment and facilitates tumor growth and metastasis. Conversely, the presence of ATP promotes a pro-inflammatory, tumor-suppressive environment. Suppression of CD73/CD39 activity and reduction of extracellular adenosine has been shown to support an antitumor immune response. Therefore, the targeting of CD73 and CD39, both individually as well as in combination with immune checkpoint inhibitors for biomarkers such as PD-1 and CTLA-4, is an emerging strategy for cancer therapeutics. CD73/CD39 have been described in multiple cell types, including tumor cells, fibroblasts, endothelial cells, tumor infiltrating lymphocytes (TILs), myeloid cells, and natural killer (NK) cells. While known to be expressed on multiple cell types, the spatial characterization of CD39 and CD73 in the tumor microenvironment (TME) is still poorly understood. Characterizing the diversity of active CD73 and CD39 populations in the tumor environment will help improve development of targeted therapies for cancer treatment. The multiplex immunofluorescence (mIF) platform MultiOmyx will be used to define the distinct populations of cells expressing CD73 and/or CD39 in the TME. MuliOmyx is a proprietary mIF platform for the visualization and characterization of up to 60 protein biomarkers in a single FFPE section. Herein we report the design and use of a novel panel of commercially-available antibodies broad enough to characterize CD39 and CD73 subpopulations in the TME of a variety of tumor indications including lung, prostate, and colon cancer. Using this panel in combination with proprietary deep-learning based image analysis, CD39 and CD73 positive cells can be characterized into different immune and TME subtypes. Understanding of the variety and phenotype of CD39 and CD73 expressing cells in the TME is crucial to define the populations being targeted by therapies for cancer treatment. Citation Format: Courtney Todorov, Kevin Gallagher, Juliana Wortman, Harry Nunns, Erinn Parnell, Eric Leones, Elaine Yeung, Blair Russell, Flora Sahafi, Qingyan Au. Characterizing CD39 and CD73 cell subtypes in the tumor microenvironment using MultiOmyx. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4696.
Abstract 6529: Early life liver proteomic signature and minerals mitigation of liver injury
Authors: Isabelle Harber, Shannon D. McClintock, Randall N. Knibbs, James Varani, Muhammad N. Aslam
Journal: Cancer Research (2023)

Abstract Background and Aims: Previous long-term murine (12- and 18-month) studies in C57BL/6 mice have demonstrated the beneficial role of Aquamin, a red marine algae-derived multi-mineral supplement containing calcium, magnesium, and 72 additional trace elements, in inhibiting liver tumor formation in mice on high-fat, Western-style diet (HFWD). Liver tumor incidence in mice on HFWD was decreased to 12% with the addition of Aquamin supplementation compared with 48% in the HFWD mice. Similarly, in mice on the low-fat diet, tumor incidence was only 16% and Aquamin further reduced it to 4%. Recently, we assessed the safety and tolerability of Aquamin in human subjects in a 90-day interventional trial and there was no evidence of potential liver harm, measured by liver enzymes. A short-term (16-week) mouse study was carried out to investigate early protein changes in the liver that may play a role in liver tumorigenesis and how Aquamin can interfere with that signature. Methods: Male MS-NASH mice were maintained on a HFWD for 16 weeks with and without red algae-derived minerals. A cohort of C57BL/6 mice maintained on a standard chow (low-fat diet) was used as a control. At the end of the in-life portion of the study, body weight, liver weight, liver enzyme levels and liver histology were assessed. Samples obtained from individual livers were subjected to Tandem Mass Tag labeling and quantitative proteomics mass spectrometry. Results: As expected, no tumors were observed at 16 weeks. Mice on the HFWD demonstrated multiple protein changes associated with dysregulated fat and carbohydrate metabolism, lipotoxicity and oxidative stress. In mice receiving Aquamin-supplementation along with the HFWD, there was reduced liver toxicity as evidenced by a decrease in levels of several cytochrome P450 enzymes and other oxidant-generating moieties. Additionally, multiple keratins, which provide cytoskeletal support were elevated. Phosphate and tensin homolog (PTEN), a tumor suppressor, was upregulated with Aquamin. There was an upregulation of several pathways implicated in tumor suppressor activity, notably keratinization, hedgehog signaling in the off-state, and regulation of PTEN stability and activity. Conclusions: The proteomic expression of the livers of HFWD mice in this short-term study explains early protein changes that may contribute to liver cancer and the potential mechanisms by which dietary minerals may mitigate such down-stream effects. Citation Format: Isabelle Harber, Shannon D. McClintock, Randall N. Knibbs, James Varani, Muhammad N. Aslam. Early life liver proteomic signature and minerals mitigation of liver injury [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6529.
Abstract 3952: Preclinical anti-tumor effects of MDM4/MDMX inhibitor XI-006 in breast cancer and prostate cancer cell lines mediated through reduced tumor cell migration
Authors: Arielle De La Cruz, Andrew George, Payton De La Cruz, Maximilian P. Pinho-Schwermann, Kimberly S. Meza, Taylor Arnoff, Ilyas Sahin, Stephanie L. Graff, Benedito A. Carneiro, Wafik S. El-Deiry
Journal: Cancer Research (2023)

Abstract MDM2 and MDM4/MDMX have emerged as potential mediators of tumor progression, organ-specific metastasis, and hyper-progression after immune checkpoint blockade therapy. While there are currently a number of MDM2 inhibitors in clinical trials, we found no pure MDM4/MDMX inhibitors under clinical investigation. Because hormone-resistant cancers pose a significant challenge for clinical intervention, the identification of translatable novel therapeutic targets remains an important goal. Analysis of triple-negative breast cancer (TNBC) and castration-resistant prostate cancer (CRPC) reveals overexpression of p53 negative regulator MDM4/MDMX as a frequent alteration in these cancers. There is an urgent need to study and target MDM4/MDMX in cancer therapy and this may ultimately include dual MDM2 and MDM4/MDMX inhibitors. However, it is clear that MDM4/MDMX is a primary oncogenic driver that requires specific therapeutic targeting. As metastasis is often observed clinically in patients diagnosed with breast and prostate cancer, we sought to expand our understanding of the metastasis reduction potential of a previously described preclinical MDM4/MDMX inhibitor, a 4-nitrobenzofuroxan derivative, XI-006 (NSC207895). In a scratch assay using breast and prostate cancer cell lines, increasing doses of XI-006 decreased tumor cell migration in a time and dose-dependent manner, demonstrating the benefit of MDMX inhibition in preventing the induction of tumor cell migration. The exact mechanism of this result remains unclear, and further investigation is needed to elucidate the impact of XI-006 on TNBC and CRPC cell proliferation and migration. Our future directions include identifying the synergistic potential of combining MDM4/MDMX inhibitor XI-006 with other cancer therapies, assessing the impact of XI-006 on immune responses in co-culture studies, and testing therapeutic efficacy in vivo. Citation Format: Arielle De La Cruz, Andrew George, Payton De La Cruz, Maximilian P. Pinho-Schwermann, Kimberly S. Meza, Taylor Arnoff, Ilyas Sahin, Stephanie L. Graff, Benedito A. Carneiro, Wafik S. El-Deiry. Preclinical anti-tumor effects of MDM4/MDMX inhibitor XI-006 in breast cancer and prostate cancer cell lines mediated through reduced tumor cell migration. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3952.